CN102088853A - Compounds for improving learning and memory - Google Patents
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- CN102088853A CN102088853A CN2009801280346A CN200980128034A CN102088853A CN 102088853 A CN102088853 A CN 102088853A CN 2009801280346 A CN2009801280346 A CN 2009801280346A CN 200980128034 A CN200980128034 A CN 200980128034A CN 102088853 A CN102088853 A CN 102088853A
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Abstract
The present invention provides a compound of Formula I: (I) and methods for improving memory in a subject by administering a therapeutically effective amount of the compound.
Description
The information of related application
The application requires the priority of No. the 61/052nd, 600, the U.S. Provisional Application submitted on May 12nd, 2008, and described provisional application is bonded to this paper by reference.
Technical background
Man memory has the multiple gene cognitive features.About 50% heritability is estimated to show that abiogenous hereditary variability has material impact for this basic brain function.The research that up-to-date candidate gene is relevant has identified that some have the genetic variation of appreciable impact for people's memory capability.Yet the success of these researchs depends on the information of preexist, and this has limited it and has differentiated the potentiality of unrecognized gene and molecular pathway.
The latest developments aspect the development of high density genotyping platform made identify some genes (particularly KIBRA gene) of being responsible for episodic memory and long-term memory behavior become possible (Papassotiropoulos etc., Science 2006,314,475; WO 2007/120955).Yet, still do not have available methods of treatment for the patient of the episodic memory of suffering from deterioration or long-term memory.Be accredited as maincenter albumen in the signal path that stimulates memory based on KIBRA, it is found that giving rho kinases 2 (ROCK) inhibitor (particularly Fasudil) can strengthen learning and memory ability (.Behavioral Neuroscience 2009 such as Huentelman, 123,218; WO 2008/019395).For the patient's of the episodic memory of realizing being suitable for suffering from deterioration or long-term memory treatment, need be used to strengthen the noval chemical compound of learning and memory.
Summary of the invention
One aspect of the present invention provides compound and salt, hydrate and the solvate of following formula I:
R wherein
1For being selected from hydrogen, C
1-6Alkyl, hydroxyl and halogen are preferably selected from hydrogen and C
1-6The member of alkyl; R
2Be C
3-8Cycloalkyl, R simultaneously
2Be positioned at 6,7 or 8 of isoquinolin part, preferably at 8; R
3For being selected from hydrogen and C
1-6The member of alkyl; And n is 0,1 or 2, preferred 1 or 2.
The present invention provide on the other hand in the subject, improve learning and memory (comprise improve for example schizoid cognitive defect of mental illness, treatment dementia for example Alzheimer disease, pik disease, volume temporo dementia (Fronto-temporal dementia), vascular dementia, kuru disease, Creutzfeldt-Jakob disease (Creutzfeld-Jakob disease) and infect the dementia that causes by acquired immune deficiency syndrome (AIDS)/HIV), improve the method for neural plasticity and/or treatment Alzheimer disease, described method comprises the formula I compound that the patient treatment of needs effective dose is arranged.
The present invention provides the method for treatment patient's anxiety, depression, bipolar disorder, unipolar disorders or posttraumatic stress disorder on the other hand, and described method comprises the formula I compound of described patient being treated effective dose.
Other purposes, feature and benefit will become apparent from following detailed description.Detailed description that provides and instantiation only are used for explanation, because multiple within the spirit and scope of the present invention changes and improvements will become apparent according to this detailed description for those skilled in the art.In addition, these examples have proved principle of the present invention, can not be contemplated to have described particularly to apply the present invention to obviously all available examples of the present invention to those skilled in the art.
The accompanying drawing summary
Fig. 1: the reaction process of synthetic 1-(1-chloro-8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.
Fig. 2: the reaction process of synthetic 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.
Fig. 3: have the kinases tabulation to the remaining binding affinity of kinase activity site bound substrates of measuring with AMBIT KinomeScan when 2-methyl-piperazine exists at 1-(8-cyclohexyl-5 isoquinolin-sulfonyl).These kinases are arranged according to the binding affinity of they and 11-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.
Fig. 4 A: the LTP by the θ burst stimulation induces.Drawn the curve of slope (maximum fEPSP amplitude 30 to 70%) with respect to the time.(arrow) induces LTP behind contrast record 15min.The short-term indication SEM of data point top.
The effect that Fig. 4 B:1 μ M 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine is induced for LTP.Draw the curve of G-bar (maximum fEPSP amplitude 30 to 70%) for the time.LTP (arrow) behind contrast record 30min induces.Black line represents to exist 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine, short-term indication SEM, n=5 repetition.
The effect that Fig. 4 C:10 μ M 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine is induced for LTP.Draw the curve of G-bar (maximum fEPSP amplitude 30 to 70%) for the time.LTP (arrow) behind contrast record 30min induces.Black line represents to exist 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine, short-term indication SEM, n=5 repetition.
The effect that Fig. 4 D:100 μ M 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine is induced for LTP.Draw the curve of G-bar (maximum fEPSP amplitude 30 to 70%) for the time.LTP (arrow) behind contrast record 30min induces.Black line represents to exist 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine, short-term indication SEM, n=5 repetition.
Detailed Description Of The Invention
The invention provides for strengthening and remember and study, and be used for the treatment of the noval chemical compound of Alzheimer disease. Compound described herein not only can be used for treating amnesia (this situation is a symptom of Alzheimer disease), and can be used for treating the cause of Alzheimer disease and can postpone the outbreak of this disease or prevent this advancing of disease. In other respects, this compound can be used for treating anxiety, depression, bipolar disorder, unipolar disorders and posttraumatic stress disorder.
The albumen relevant with memory of two most studies of possibility is PKC and cAMP-responsive element binding protein (CREB). The PKC family member since they cross in several crucial brains zone express, memory program that their participate in crossing over several thing classes, they with people that the space learning defective is associated in active aspect relevant variation of age and the last PKC evidence that suppresses to damage learning and memory, (Micheau allegedly plays a role in memory, J.﹠ Riedel, G.Cell Mol Life Sci 55,534-48 (1999); Pascale, the .Mol Neurobiol 16 such as A., 49-62 (1998); Sun, M.K.﹠ Alkon, D.L.Curr Drug Targets CNS Neurol Disord 4,541-52 (2005); Birnbaum, the .Science such as S.G. 306,882-4 (2004); Etcheberrigaray, the .Proc Natl Acad Sci USA 101 such as R., 11141-6 (2004); Ruiz-Canada, the .Neuron such as C. 42,567-80 (2004)). CREB comprises as the support of memory related gene that its long time-histories in sea slug (sea hare (Aplysia)) promotes and the long time-histories in rodent strengthen really tailor-madely use, real example that the induced destruction of CREB function has been blocked mouse memory and for the compound of the change CREB activity exploration (Josselyn as memory enhancers, S.A.﹠ Nguyen, P.V.Curr Drug Targets CNS Neurol Disord 4,481-97 (2005); Carlezon, W.A. waits .Trends Neurosci 28,436-45 (2005); Cooke, S.F.﹠ Bliss, T.V.Curr Opin Investig Drugs 6,25-34 (2005); Josselyn, S.A., Kida, S.﹠ Silva, A.J.Neurobiol Learn Mem 82,159-63 (2004); Martin, K.C.Neurobiol Learn Mem 78,489-97 (2002); Lonze, B.E.﹠ Ginty, D.D.Neuron 35,605-23 (2002); Si, K., Lindquist, S.﹠ Kandel, E.R Cell 115,879-91 (2003); Chen, the .Neuron such as A. 39,655-69 (2003)). In addition, have the evidence of auxiliary (mounting) genetic aspect to support the effect of other albumen in memory, these albumen comprise HTR2A, BDNF and PKA (Alonso, the .Learn Mem 12 such as M., 504-10 (2005); Bramham, C.R.﹠ Messaoudi, E.Prog Neurobiol 76,99-125 (2005); Papassotiropoulos, the .Neuroreport such as A. 16,839-42 (2005); De Quervain, the .Nat Neurosci 6 such as D.J., 1141-2 (2003); Reynolds, C.A. waits .Neurobiol Aging 27,150-4 (2006); Arnsten, A.F. waits .Trends Mol Med 11,121-8 (2005); Quevedo, the .Behav Brain Res 154 such as J., 339-43 (2004)).
KIBRA is accredited as the binding partner (Kremerskothen of people's isoform of the stem of noble dendrobium high-alkali (dendrin) (a kind of synaptic plasticity infer conditioning agent) in yeast two-hybrid screening recently, J. etc., Biochem.Biophys.Res.Commun.300,862 (2003)). The form of the brachymemma of expressing in hippocampus lacks a 223aa and comprises sequence and protein kinase C (PKC) ζ-interaction domain (de Quervain of C2 spline structure territory, rich glutamic acid, D.J. etc., Nat.Neurosci.6,1141 (2003)). PKC-ζ participates in memory and forms and participate in fixed (consolidation) (Bookheimer, S.Y. etc., N.Engl.J.Med.343,450 (2000) that long time-histories strengthens; Milner, B.Clin.Neurosurg.19,421 (1972)). The C2-spline structure territory of KIBRA is similar to the C2 domain of synaptotagmin, and it is considered in the synaptic versicle exocytosis as main Ca2+Sensor play a role (Freedman, M.L. etc., Nat.Genet.36,388 (2004); Schacter, D.L.﹠ Tulving E.Memory systems (MIT Press, Cambridge, 1994)). The KIBRA haplotype district group (block) that the memory of describing among the WO 2008/019395 is relevant and SNP mapping (map) are in the KIBRA of the brachymemma that comprises C2-spline structure territory and PKC-ζ-interaction domain. In a word, evidence shows that KIBRA works in normal person's memory behavior.
In addition, KIBRA has the high expressed amount in brain, and it regulates Ca2+, for the PKC substrate and be synapsin. Some other heredity is found to have made it possible to RhoA/ROCK is accredited as target spot in the memory, Fasudil is accredited as strengthen memory, study and cognitive conditioning agent (the .Behavioral Neuroscience 2009,123,218 such as Huentelman; WO 2008/019395). CLSTN2 has the high expressed amount in brain, it regulates Ca2+And be synapsin. CAMTA1 has the high expressed amount in brain, it regulates Ca2+And be transcription factor. SEMA5A has the high expressed amount and participates in the aixs cylinder guiding in the brain of growing. TNR has the high expressed amount in brain, it participates in ECM and assists cynapse to keep. At last, NELL2 also has the high expressed amount in brain, and its is assisted neure growth and shows the LTP of enhancing but weaken the study of HPF mediation. In addition, the in situ hybridization of each gene target spot demonstrates the expression in hippocampus of mice.
The RhoA/ROCK path in the normal memory function and the importance in Alzheimer cognitive descend (with other possible amnesia) can not be underestimated. Many destructive illnesss comprise amnesia as main clinical characteristics, and the RhoA/ROCK path may play a role aspect overall seriousness, progress or the pathology of these illnesss in the situation of these illnesss. Even minimum extension will be useful to the patient who suffers from these illnesss before the amnesia outbreak.
Available hundreds of known kinase carries out abreast avtive spot and relies on competitive binding assay (Fabian etc., Nat Biotechnol.2005,23,329; Karaman etc., Nat Biotechnol.2008,26,127) with measure compound how with being combined with unexpected kinases of expection. These class methods make it possible to assess the specificity of inhibitors of kinases.
Compound of the present invention only relies in the competition binding analysis for few relatively kinases (for example CSNK1E, CSNK1A1L, CSNK1D, MERTK, SLK, IRAK1, STK10, MAPK12, PHKG2, MAPK11, MET, AXL, STK32B, AURKC, CLK3, RPS6KA6, PDGFRB, KDR, CDK2, referring to Fig. 3) at avtive spot and demonstrates strong (surpassing 50%) combination.Therefore these compounds are used as the specificity inhibitors of kinases.They are fit to treatment and relevant illness and the disease of these kinases (being CSNK1E, CSNK1A1L, CSNK1D, MERTK, SLK, IRAK1, STK10, MAPK12, PHKG2, MAPK11, MET, AXL, STK32B, AURKC, CLK3, RPS6KA6, PDGFRB, KDR and CDK2).
Give the influence of compound in the body in order to measure for memory behavior, can use multiple known animal experiment, Sacktor disc test for example, this test relies on a kind of special shape (Pastalkova etc. that activity site that acquistion and lasting hippocampus rely on the test advantage of recalling is avoided (active place avoidance) for having quick hippocampus, Science 2006,313,1141).This equipment is by the platform of the open slow rotation of indoor environment is formed.Can be to this platform energising when animal runs into predefined district.Rotation is brought animal into the electric shock district, and this animal learns to avoid electric shock by the non-electric shock district around initiatively moving to fast.The another kind of memory test may be the Morris water maze in the body, this labyrinth is developed as study, memory and the arrival of test rat at first only by its ability (Morris etc. with respect to place in the space of the position qualification of (extramaze) clue outside the labyrinth, distally, J Neurosci Methods 1984,11,47).Perhaps, can use the spiral arm labyrinth to come the memory of test animal.This labyrinth is made up of for example eight overhead arm around octagonal central platform.Animal can utilize outside the labyrinth visual cues to pass through by this labyrinth as the location boundary mark.Four arms at random with little food ball dress bait as award and in addition four arms do not adorn bait.Make animal go to the position of exploring this labyrinth and remembering the arm of dress bait.In the test subsequently, run into the arm of no bait and made reference promnesia, enter identical arm once more and made work promnesia, with the dress bait arm that arrived before entering once more by note by note.Advantageously, the spiral arm labyrinth can be used for test job memory simultaneously and spatial memory.Other known behavior animal experiments for example T-labyrinth, open field or object identification can be used for assessing the animal memory by those skilled in the art.This type of in vivo studies can be used to some animal subgroup for example geriatric animals, disease model animal etc., so that specifically be evaluated at memory and memory reinforced effects in this type of subgroup.A kind of classical conditioning (conditioning) form is frightened conditioning.This belongs to a kind of model of studying the emotion learning and memory.The conditioning meaning is the pairing of conditional stimulus (for example light or tone) and unconditioned stimulus (for example gentle electric shock).Unconditioned stimulus causes fear reaction separately.Animal also shows fear reaction to independent conditional stimulus after repeating the test of matching several times.This is known as condition and replys.The pairing of above-described different stimulated is also referred to as indicative frightened conditioning, and the frightened conditioning of situation (contextual) has been described the fear reaction to test cell itself.Indicative frightened conditioning is for the brain structure sensitivity that is called as amygdaloid nucleus, and the reaction of the situation that takes place seems more responsive for hippocampus.Frightened conditioning example in the animal and active and passive avoidance example all can be used for proving the study of enhancing.This type of in vivo studies can be used to some animal subgroup for example geriatric animals, disease model animal etc., so that specifically be evaluated at memory and memory reinforced effects in this type of subgroup.
Long time-histories strengthens the effect of (LTP) can be by in-vitro measurements, this effect be considered to usually with remember relevant.Stimulation afferent neuron or afferent neuron cell compartment cause that the neuron or the neuronal cell zone that are positioned at the downstream produce film potential.At least a few hours are strengthened by long time-histories this type of film potential afterwards stimulating afferent neuron (for example with the short battle array of θ rapid pulsation mode).Therefore, LTP is considered to the memory of cellular level.Can use about the neuron of cultivating with test compound and assess the potential of this compound enhancing memory (generally referring to Cooke and Bliss with the electrophysiology LTP measurement of false neuronic comparison of cultivating, Brain, 2006,129 (1659), it is bonded to this paper by reference).
Use the organotypic slice culture of rat hippocampus and concentration washing in 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine, observe the blocking-up fully that LTP-induces to increase.On the contrary, in the contrast section of not using 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine, observe LTP and be induced to about 140% of pre-irritation level.The EPSP slope increases to some extent when removing this compound, and when 100 μ M concentration the most obvious and very strong (referring to Fig. 4).This is a brand-new discovery known to the inventor.The LTP abduction mechanism that looks like cell is activated after LTP stimulates but these mechanism are covered or blocked by this compound.The removal of this compound has discharged this kind blocking-up and this system has excessive (overshooting) reaction.LTP this initially cover may for for example by the activation that stops the chloride channel that strengthens higher film potential realize-though NMDA-and AMPA-acceptor be activated by this LTP induction scheme.In case Cl
-Passage inactivation, EPSP slope just change (" start brake and drive (driving with the brakes on) " and decontrol brake at certain point) significantly.
Therefore, except strengthening memory and cognitive effect, compound of the present invention can be used for the more complicated adjusting activity in cognitive and memory form.This can comprise the enhancing that for example is used for by only selective memory (with respect to other memories) that stress (post traumatic stress) obstacle after wound experience, extremely sad and the wound that other inducements cause, for example with respect to the just memory (positive memories) of the enhancing of negative memory (negative memories).Therefore, the compound of formula I can be used for illness and the disease of treatment as anxiety, depression, bipolar disorder, unipolar disorders and posttraumatic stress disorder (PTSD).
Generally believe as memory and form and the process of learning foundation comprises that the motility of the structure plasticity of neuroid and dendron or sour jujube (spine) is (referring to for example Tada ﹠amp; Sheng, Curr Opin Neurobiol., 2006,16,95 summary).Known neural process grow the influence that is subjected to Rho GTP enzyme (family of Small GTPases has member Rho, Rac and Cdc42).Rho GTP enzyme for the effect of actin cytoskeleton and well-known, is the important conditioning agent of cell mobility and synaptic plasticity with it therefore.Rho activates Rho kinases (ROCK) with its activated GTP combining form, and ROCK activates myosin light chain then, causes that cytoskeleton is reset and the inhibition axon growth.Observing in undifferentiated PC12 cell ROCK inhibitor (such as Fasudil) increases neural process and grows (Zhang etc., Cell Mol Biol Lett., 2006,11,12).To have the effect that potential ROCK suppresses the test compound of ability in order analyzing, can to measure elementary (primary) hippocampal neuron neurite lengths (and contrasting the not check analysis of this compound) in having the cell culture of test compound.But the also increase of energy measurement complexity of increase (Sholl analysis) except length.This kind shows the prominent compound that grows that can excite nerve and can be used for the illness that needs strengthen brain plasticity and cognition.
The familial form of Alzheimer disease (AD) and frontotemporal dementia (FTD) and the evaluation of cause of disease mutator gene have caused the generation of the transgenic animal model of these diseases.Actor crucial among the AD is amylaceous precursor protein (APP).Crossing the mouse of expressing sudden change APP is the most widely used model (Ashe, Learn Mem.2001,8,301 that are used for studying the AD memory impairment; Chapman etc., Trends Genet.2001,17,254; Goetz ﹠amp; Ittner, Nat Rev Neurosci.2008,9,532).These mouse are carried the different variants of amylaceous precursor protein (APP) and work as these precursor proteins at the AD patient (animal (Hsiao etc. that for example have so-called Sweden type sudden change (Tg2576), Science 1996, when significantly occurring 274,99)), develop in time and amnesia.These animal models can be used for testing potential memory and strengthen the effectiveness of compound to disease model in the body.
To comprise for example following illness from treatment of the present invention and benefited pathology or the neuropathology of diagnostic application:
The disease of maincenter kinematic system comprises influencing paralysis, PBP, familial spastic, Duchenne-Arandisease, ALS and variant, dentato rubral atrophy, olvopontocerebellar atrophy, paraneoplastic cerebellar degeneration and dopamine toxicity on the degeneration of basal nuclei illness (Huntington, hepatolenticular degeneration, SND, the sex change of cortex basal ganglion), tourette's syndrome, Parkinson's, the carrying out property nuclear;
Influence the disease of sensory neuron, for example Friedreich ataxia, diabetes, peripheral nerve disease, retinal neurons sex change;
The disease of edge and cortex system, for example brain amyloidosis, pik atrophy, rett's syndrome;
The neurodegeneration pathology that relate to multi-neuron system and/or brain stem, comprise the relevant dementia of Alzheimer disease, acquired immune deficiency syndrome (AIDS), Leigh disease, diffusivity lewy body disease, epilepsy, MSA, Ge-Ba syndrome, lysosomal storage disease for example lipofuscinosis, Down syndrome sex change in late period stage, A Erpo disease, CNS sex change cause dizzy;
The relevant pathology of neuronal death that bring out with hypoevolutism and learning disorder and Down syndrome and oxidative stress;
With pathology old and feeble and long term alcohol or drug abuse appearance, comprise the neuronal degeneration of for example following in crapulent locus coeruleus, cerebellum, the cholinergic base forebrain (cholinergic basal forebrain); Follow the sex change (causing cognition and movement disorder) of old and feeble cerebellar neuron and cortical neuron and the neuronic sex change of basal nuclei (causing movement disorder) of accompanied by long-term amphetamine abuse;
The pathological change that causes by focus wound (for example apoplexy, focus ischemic, vascular function are complete, hypoxie-ischemic encephalopathy, hyperglycaemia, hypoglycemia, CHT or direct wound);
The pathology that occur as the negative side effect of the medicine of treatment and therapy (for example reply anticonvulsion dosage glutamate receptor the NMDA class antagonist, chemotherapy, antibiotic etc. cingulum and in smell the sex change of (entorhinal) cortical neuron); With
Study can not, for example ADD, ADHD, dislexia, dysgraphia, dyscalculia, movement disorder and information processing obstacle.
I. definition
Memory system can broadly be divided into four main types: incident, semantic, work and (Hwang, D.Y.﹠amp program; Golby, A.J.Epilepsy Behav (2005); Yancey, S.W.﹠amp; Phelps, E.A.J Clin Exp Neuropsychol 23,32-48 (2001)).Episodic memory is meant record and recalls system about the autobiography information of the experience that occurs in specified place and time.The common factual knowledge (for example provincial capital of Arizona) that semantic memory system stores and place and time are irrelevant.Working memory relates to the provisional maintenance and the use of information, and nondeclarative memory is automatic and the activity of the learning skill of running unconsciously usually.Episodic memory, semantic memory and working memory are essentially (illustrative) of clear and definite (absolute) and statement and nondeclarative memory can be clear and definite or implicit, but total declarative (Tulving of right and wrong, E.Oxford University Press, New York, 1983); Budson, A.E., Price, B.H.Encyclopedia of Life Sciences (Macmillan, Nature Publishing Group, London, 2001); Budson, A.E.﹠amp; Price, B.H.N Engl J Med 352,692-9 (2005); Hwang, D.Y.﹠amp; Golby, A.JEpilepsy Behav 8,115-26 (2006)).
The usual aging state and the morbid state of infringement memory include but not limited to, neurodegeneration obstacle for example, head and cerebral trauma, genetic block, infectious disease, inflammatory disease, pharmacotherapy, medicine and alcohol disorder (disorder), cancer, metabolic disorder, mental retardation and learning and memory obstacle, for example old and feeble relevant amnesia and old and feeble relevant memory impairment (AAMI), Alzheimer disease, Protein tau disease (tauopathies), PTSD (irritability syndrome after the wound), slight cognitive decline, ALS, Huntington chorea, amnesia, the B1 deficiency disease, schizophrenia, depression and bipolar disorder, apoplexy, hydrocephaly, subarachnoid hemorrhage, vascular function is incomplete, brain tumor, epilepsy, Parkinson's, cerebral microvascular disease (Meyer, R.C. wait .Ann N Y Acad Sci 854,307-17 (1998); Barrett, A.M.Postgrad Med 117,47-53 (2005); Petersen, R.C.J Intern Med 256,183-94 (2004); Calkins, M.E. wait .Am J Psychiatry 162,1963-6 (2005)), the pain medication, chemotherapy (" chemotherapy brain (chemobrain) "), anoxic is (for example by heart-lung machine, anesthesia or nearly drowning cause), dementia be (blood vessel, the volume temporo, the Louis body, semantic, carrying out property of primary aphasia, the pik disease), benumb on the carrying out property nuclear, the sex change of cortex base, Hashimoto (Hashimoto) encephalopathic, ADD, ADHD, dislexia and other study can not, Down syndrome, fragile X syndrome, Turner syndrome and fetal alcohol syndrome.Except disease, carrying out property amnesia is the common accessory substance of aging course.
The slight cognitive decline of term (MCI) is used to refer at normal cognitive function and develops into intermediate zone (Winblad .J Intern Med 256 such as B., 240-6 (2004)) between the possible clinically AD.Used multiple standards to limit MCI, yet they have two main themes basically: (1) MCI refers to have the non-dementia patients of measurable cognitive defect of certain form and the high risk clinical syndrome that (2) these patients' representatives have the clinical dementia of developing into.
Phrase " improves and learns and/or memory " parameter that refers to improve or strengthen at least a demonstration learning and memory.Improving or strengthening is parameter change at least 10%, optional at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200% etc.The improvement of learning and memory can be measured by any method known in the art.For example, the compound that improves learning and memory described herein can by use the screening of Morris water maze (referring to, for example material and method part).Also referring to Gozes etc., Proc.Natl.Acad.Sci.USA 93:427-432 (1996).Also can use any method described herein or other known method (for example Randt recall tests, Wechler memory tolerance, forward numerical span (Forward Digit Span) test or California verbal learning test) screening (screen) memory and study for those skilled in the art.
Term " space learning " refers to understand individual environment and where what object this need know.It also relates to understands and uses information about the relation between the multiple clue in the environment.The space learning ability of animal can be tested by making position that animal learning rewards and usage space clue remember these positions.For example, can use spiral arm labyrinth (promptly learn which arm food is arranged) Morris water maze (be learning platform where) to come test space study.For carrying out these tasks, animal is used the clue (position of object, smell etc.) from the test room.For the mankind, but also test space study.For example can allow the subject draw a width of cloth picture, this picture is removed then.Allow the subject according to the memory identical picture that draws then.The picture that the subject drew has afterwards reflected the degree of subject's space learning.
Study can not be meant be revealed as obtain and use listen, say, the general term of (heterogeneous) group that exists the disease of significant difficulties heterogeneous aspect reading and writing, reasoning or the mathematical ability.Study can not comprise ADD, ADHD, dislexia, dysgraphia, dyscalculia, movement disorder and information processing obstacle.
" administration " used herein be meant oral administration, with in suppository, local contact, parenteral, intravenous, the peritonaeum, in the intramuscular, damage, mouthful in, in the nose or subcutaneous administering mode administration, intrathecal drug delivery or to subject's implantation slow release equipment (for example small-sized osmotic pump).
Term used herein " alkyl " be meant have the straight or branched of specifying carbon number, saturated, aliphatic group.For example, the C1-C6 alkyl includes but not limited to, methyl, ethyl, propyl group, butyl, amyl group, hexyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group etc.
Term used herein " halogen " is meant fluorine, chlorine, bromine and iodine.
Term used herein " heterocycle " is meant the loop systems with 5 to 8 annular atomses and 2 nitrogen heteroatoms.For example be used for heterocycle of the present invention and include but not limited to, pyrazolidine, imidazolidine, piperazine and high piperazine.Heterocycle of the present invention is that N-connects, and meaning promptly connects by a ring hetero atom.
Term used herein " hydrate " is meant the compound of at least one hydrone of complexing.But 1 to 10 hydrone of compound complexing of the present invention.
The form that some compound of the present invention can non-solventization and the form (form that comprises hydration) of solvation exist.Usually, the form and the expection that are equivalent to non-solventization of the form of solvation is contained in the scope of the present invention.Some compound of the present invention can many crystallizations or the existence of amorphous state form.Usually the purposes that all physical form (physical form) are considered for the present invention be equivalence and expection within the scope of the invention.
Term used herein " salt " is meant the acid salt or the basic salt of the compound that uses in the method for the present invention.The illustrative example of pharmaceutically acceptable salt is inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid etc.) salt, organic acid (acetate, propionic acid, glutamic acid, citric acid etc.) salt, quaternary ammonium (methyl iodide, ethyl iodide etc.) salt.It is nontoxic should understanding this pharmaceutically acceptable salt.Other information about suitable pharmaceutically acceptable salt can be referring to Remington ' s Pharmaceutical Sciences (Remington pharmacology), 17th ed., Mack Publishing Company, Easton, Pa., 1985, it is bonded to this paper by reference.
The pharmaceutically acceptable salt of acid compound of the present invention is the salt that forms with alkali, be for example alkali metal salt and alkali salt of cationic salt, for example sodium salt, lithium salts, sylvite, calcium salt, magnesium salts and ammonium salt, for example ammonium, trimethyl ammonium, diethyl ammonium and three-(methylol)-methyl-ammonium salt.
Similarly, the acid-addition salts for example acid-addition salts of inorganic acid, organic carboxyl acid and organic sulfonic acid (for example hydrochloric acid, methanesulfonic acid, maleic acid) also is possible, and prerequisite is the described structure of basic group (for example pyridine radicals) component part.
The neutral form of described compound can produce again by salt is contacted and separates parent compound with conventional method with alkali or acid.Parent form at (for example solvability in polar solvent) this compound aspect some physical property is different from various salt forms, but is equal to the parent form of described compound for the described salt of purpose of the present invention.
Term used herein " subject " is meant for example mammal of animal, includes but not limited to primate (for example people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc.Preferred subject behaves.
Term used herein " treatment effective dose " or " treatment effective dose or dosage " or " treatment is amount or dosage fully " or " effectively or fully measuring or dosage " are meant the dosage of the therapeutic action that produces the administration expection.Definite dosage will depend on the purpose of treatment, and can by this area use the technical staff of known technology determine (referring to, Lieberman for example, Pharmaceutical Dosage Forms (vols.1-3,1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999) and Remington:The Science and Practice of Pharmacy (pharmaceutical science with put into practice), 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams ﹠amp; Wilkins).In sensitized cell, the treatment effective dose often can be lower than the conventional therapy effective dose that is used for non-sensitized cell.
II. using method
The invention provides the method for improving memory and study by compound or its salt, hydrate and the solvate of giving construction I.Shown in following examples, this compound is used for strengthening memory, improves neural plasticity and/or treatment Alzheimer disease.This compound can be by for example mouth, parenteral or nasal administration.For long term administration, can use than low dosage.Compound of the present invention can be used in combination with the treatment morbid state with other drug or improve learning and memory.And this compound can be used as special and effective ROCK inhibitor.Therefore, they are fit to the relevant disease of treatment ROCK, for example vasospasm after the subarachnoid hemorrhage.
III. compound
The invention provides the compound of formula I:
R wherein
1For being selected from hydrogen, C
1-6The member of alkyl, hydroxyl and halogen for example is selected from hydrogen and C
1-6Alkyl; R
2Be C
3-8Cycloalkyl, R simultaneously
2Be positioned at the position 6,7 or 8 of isoquinolin part, for example be positioned at position 8; R
3For being selected from hydrogen and C
1-6The member of alkyl; And n is 0,1 or 2, for example 1 or 2.R in certain embodiments
1Or R
3Be alkyl group, this group is C
1-3Alkyl.The compound of formula I also can be its salt, hydrate and solvate.
Usually, the compound of formula I and its salt and hydrate can use the methodology fully determined and prepare based on those skilled in the art's general knowledge.These are described in, and for example United States Patent (USP) the 4th, 678, and No. 783 and the 5th, 942, in No. the 187th, 371, No. 505 and the European patent, these full patent texts are bonded to this paper by reference.The more detailed methodology of representative compounds of the present invention is described in detail below.
In one embodiment, this compound is the compound of following formula:
Or the compound of following formula:
Or the compound of following formula:
Among other embodiment, this compound is 1-(1-chloro-8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine or 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.The illustrative synthetic method of these compounds is described in Fig. 1 and Fig. 2.Relevant compound can prepare with similar method.
IV. fill a prescription
Compound of the present invention can be prepared with different ways well known by persons skilled in the art.Pharmaceutical acceptable carrier depends in part on the concrete composition that gives, and depends on the concrete grammar that is used to give said composition.Therefore, for pharmaceutical compositions of the present invention exist a variety of suitable prescriptions (referring to, Remington ' s Pharmaceutical Sciences (Remington pharmaceutical science) for example, 20
ThEd., 2003, see above).Effectively prescription comprises mouthful and the prescription of nose, is used for the prescription of parenteral and is mixed with the composition of long-term release.
Being suitable for peroral administration prescription can be by (a) liquid solution, and for example the compound of the present invention of effective dose is suspended in the dilution (for example water, salt solution or PEG 400); (b) capsule, sachet, depot formulation (depot) or tablet respectively comprise the active component of scheduled volume, exist with the form of liquid, solid, particle or gelatin; (c) suspension in suitable liquid; (d) suitable emulsion and (e) patch form.Medicament forms can comprise one or more in lactose, sucrose, mannitol, sorbierite, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silica, talcum, dolomol, stearic acid and other excipient, pigment, filler, adhesive, thinner, buffer, humidizer, preservative, fumet, dyestuff, disintegrant and the pharmacy compatibility carrier.Lozenge form can be included in the active component in the flavouring (flavor) (for example sucrose), and pastille (pastille), pastille comprises active component in inert base, inert base is gelatin and glycerine or sucrose and gum Arabic emulsion, gel etc. for example, also contains carrier known in the art except that active component.
Pharmaceutical formulations is preferably unit dosage forms.Be subdivided into the unit dose of the active component that comprises appropriate amount with this kind form said preparation.This unit dosage form can be the preparation of packing, and this packing comprises the preparation of discrete magnitude, for example Bao Zhuan tablet, capsule and the powder in bottle or in ampoule.And this unit dosage form can be capsule, tablet, cachet or lozenge itself or it can be any of these formulation of the proper number that exists with packaged form.Said composition can also comprise (if needed) other compatibility therapeutic agents.Preferred drug substances can be sent compound of the present invention with the slowly-releasing prescription.
Be used for pharmaceutical formulations of the present invention and also comprise long-term release formulation.In some embodiments, be used for long-term release formulation of the present invention and be described in United States Patent (USP) the 6th, 699, in No. 508, these prescriptions can be according to United States Patent (USP) the 7th, 125, No. 567 preparations, and two patents all are bonded to this paper by reference.
This pharmaceutical formulations is delivered to mammal usually, comprises people and inhuman mammal.Use the inhuman mammal of this method treatment to comprise performing animal (being Canidae, cat family, Muridae, rodent and Lagomorpha) and agricultural animal (ox, horse, sheep, pig).
When putting into practice method of the present invention, this pharmaceutical compositions can use separately or be used in combination with other treatment agent or diagnosticum.
V. administration
Compound of the present invention can be as required the frequency administration, per hour comprise once, once a day, weekly or every month once.The compound that uses in the method for pharmacy of the present invention is with the extremely predose administration of about 1000mg/kg of about 0.0001mg/kg every day.Spendable every day dosage range for about 0.01mg/kg to about 500mg/kg, perhaps about 0.1mg/kg is about 200mg/kg or about 1mg/kg about 100mg/kg or about 10mg/kg about 50mg/kg extremely extremely extremely.Yet dosage can change according to the order of severity of the illness of needs of patients, treatment and the compound of use.For example, can consider that the disease type of particular patient diagnosis and stage also determine dosage empirically.The dosage that gives the patient in the context of the present invention should be enough to pass in time the useful therapeutic response of generation in the patient.The size of dosage also will decide by existence, the nature and extent of following specific compound to give any disadvantageous side reaction of particular patient.Decision is used for the suitable dose of concrete condition in the technical scope of practitioner.Usually, treatment begins to use smaller dose less than the optimal dose of this compound.Afterwards, dosage increases until the optimum efficiency that reaches under these situations with little increment.If needed, for convenience, total daily dosage can be separated and administration in batches in a day.Dosage can give or give every other day every day, by treatment doctor decision.But dosage also systematicness or continuity ground long period (several weeks, several months or several years) gives, for example the micropump by using subcutaneous capsules, sachet or depot formulation, implantation or give by patch.
This pharmaceutical compositions can comprise partly in many ways, give the patient in parenteral, intravenous, intracutaneous, subcutaneous, intramuscular, per rectum, per rectum or the peritonaeum.Preferred this pharmaceutical compositions through parenteral, partly, intravenous, intramuscular, subcutaneous, per os or intranasal (for example by suction) give.
When putting into practice method of the present invention, this pharmaceutical compositions can use separately or be used in combination with other treatment agent or diagnosticum.One or more medicines that the other drug that is used for assembled scheme of the present invention could be given or be used for this assembled scheme respectively can be given together, for example with the form of mixture.When one or more medicines gave respectively, the time and the program that give every kind of medicine can change.Other therapeutic agent or diagnosticum can with compound of the present invention simultaneously, separate or give at different time.
VI. embodiment
The preparation of embodiment 1:1-(1-chloro-8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine
1-(1-chloro-8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine is according to synthetic schemes manufacturing shown in Figure 1.
The preparation of embodiment 2:1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine
1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine is according to Fig. 2 manufacturing.Be dissolved in 112g2-bromobenzaldehyde and 61ml n-butylamine in the 350ml toluene and use reflux condenser heating 3h, stir in environmental temperature then and spend the night.Solvent is distilled out N-(the 2-bromine benzal) butane-1-amine that obtains the red oily of 144g.
With 41g N-(2-bromine benzal) butane-1-amine solvent in anhydrous THF of 450ml and 2.2g manganous chloride (II).Dropwise add 265ml cyclohexyl bromination magnesium at 0-5 ℃ after being cooled to 0 ℃.Behind 2 ℃ of stirring 1h, dropwise add the saturated ammonium chloride solution of 150ml at 2-7 ℃.With solution extracted with diethyl ether three times.Wash the organic facies that merges and use dried over sodium sulfate with the 200ml saturated nacl aqueous solution.Remove solvent and residue is carried out chromatographic purifying, obtain the 2-cyclohexyl benzene formaldehyde of 26g yellow oily.
Be dissolved in 26g 2-cyclohexyl benzene formaldehyde and 20.1g 2-glycyl aldehyde dimethylacetal in the 200ml toluene and use the dehydrator heating.After removing solvent residue is dissolved among the anhydrous THF of 100ml.Dropwise add the 18.2ml ethyl chloroformate and solution is stirred 5min again at-10 ℃.Add the 22.6ml Trimethyl phosphite and solution is stirred 16h again in environmental temperature.After solvent distillated residue is concentrated with toluene.In ar gas environment, be dissolved in the 450ml anhydrous methylene chloride oiliness residue and the careful 126ml of adding titanium tetrachloride.Use reflux condenser heating 36h to add 1L 20% sodium hydroxide solution then solution.Solid matter filtered and the water of filtrate is merged with twice of 200ml dichloromethane extraction and with the organic facies of filtrate.With organic facies 3N hcl as extraction agent three times that merge.The water that merges also is adjusted to alkaline pH with 10% sodium hydroxide solution twice with the 100ml washed with dichloromethane.The organic facies that merges with water after the 200ml dichloromethane extraction three times and saturated nacl aqueous solution washing.Obtain 4.5g yellow oily 8-cyclohexyl-isoquinolin with solvent being distillated after the dried over sodium sulfate.
1g 8-cyclohexyl-5-isoquinolin is dissolved in the ice-cold sulfuric acid of 5ml, dropwise adds 5ml oleum and further cooling then.After 80 ℃ are stirred 2h, be poured over solution on the frozen water and, obtain the brownish solid 8-cyclohexyl of 1.2g-5-isoquinolin-sulfonic acid with sedimentation and filtration, with cold water washing and vacuum drying.
1.2g 8-cyclohexyl-5-isoquinolin-sulfonic acid is suspended in the 15ml thionyl chloride.After adding 0.1ml DMF solution is heated 2h with reflux condenser.Vacuum condition goes down to desolventize and the oiliness residue is concentrated twice with carrene.The foam residue is suspended in the 10ml frozen water and with saturated sodium bicarbonate solution the pH value is adjusted to pH6-7.With the dried over mgso organic facies and at 0 ℃ organic facies dropwise is added to the 4.95g tert-butyl group oxygen carbonyl-solution of 3-methyl piperazine in the 20ml carrene with after the 20ml dichloromethane extraction.0 ℃ stir 1h and after environmental temperature stirs 5h with solution with the 20ml water washing, with dried over mgso and concentrated.Residue is dissolved in 50ml 7N hydrochloric acid/isopropyl alcohol and stirs 2h in environmental temperature.Solution concentration is become dried residue and it is dissolved in the saturated sodium bicarbonate solution.Use dried over mgso with dichloromethane extraction water 3 times and with the organic facies that merges then with the 30ml water washing.Remove solvent afterwards with residue chromatography purifying.Obtain 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine of 470mg colourless foam like this.
Embodiment 3: the kinases specificity analyses
Based on the competition binding analysis of quantitative measurment test compound with part competitive ability fixing, the avtive spot orientation, might compete effect (KinomeScan, Ambit, San Diego for diversified kinases by parallel detection test compound, CA, USA; Fabian etc., Nat Biotechnol.2005,23,329).Inhibition selectivity based on the possible evaluation test compound of this analysis.This analysis is carried out with 10 μ M concentration with 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.As the result of this analysis can obtain since with the cultivation of test compound, for 400 kinds of kinase whose each the part competition percentages of avtive spot orientation that surpass of this test.Fig. 3 has listed the kinases of arranging according to combining with 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine (compd A).Only be found in kinase c SNK1E, CSNK1A1L, CSNK1D, MERTK, SLK, IRAK1, STK10, MAPK12, PHKG2, MAPK11, MET, AXL, STK32B, AURKC, CLK3, RPS6KA6, PDGFRB, KDR, CDK2 with strong combination the (greater than 50%) of 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.Therefore, this compound is inhibitors of kinases very selectively.
Embodiment 4: external LTP analyzes
LTP is considered to be used for the suitable external model of assess memory function.Therefore, this makes the memory of possibility analytical test compound (compound for example of the present invention, for example 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine) strengthen potentiality.Use hippocampal slices to experimentize from the Wistar rat in age in 3-4 week.Rat is passed through sacrificed by decapitation without anesthesia in advance.Take out rapidly brain and it is soaked in the ice-cold synthetic cerebrospinal fluid (ACSF), this cerebrospinal fluid comprises: NaCl (124mM), KCl (5mM), Na2HPO4 (1.2mM), NaHCO3 (26mM), CaCl2 (2mM), MgSO4 (2mM) and glucose (10mM), and close oxygen (carbogen) (95%O2,5%CO2) with carbon and continue bubbling.Be cut into 400 μ m slabs and in ACSF, cultivate 1h at least, opening entry then with vibratome then in room temperature.The compound of all uses with the concentration dilution of needs in ACSF, and all in fresh preparation from the 100mM stock solution on the same day of record.In order to ensure the suitable solvability of these compounds, stock solution is prepared with DMSO.For record, section is transferred in the 4-groove biopsy chamber (Synchroslice, Lohmann Research Equipment), can write down 4 brain sections simultaneously like this.Each section is placed immersion type biopsy chamber separately, and this biopsy chamber constantly pours into the speed of 2ml/min with the ACSF or the ACSF of control temperature (34 ℃).Visual observation control by camera arrangement places Schaffer side shoot (collateral) with bipolar stimulation electrode (Rhoades) and uses with 0.05Hz to continue 200 μ s and amplitude is the single biphasic electro photoluminescence of 200 μ A.Under vision control, platinum/tungsten electrode is reduced in the CA1 dendritic layer stabilized amplitude then up to the fEPSP that reaches record.At least the record of 10min is after the phase, and for each section, the input-output relation between stimulation amplitude and the fEPSP amplitude obtains respectively.For record, separately select stimulation amplitude so that the fEPSP that obtains shows from 50% of the peak swing of IO curve for each section.For inducing LTP, use the short battle array of θ fast-pulse 10 times.Each pulse is made up of 4 overlap biphasic impulses that schedule to last 200ms, amplitude 600 μ A, stimulus intervals 10ms.Pulse spacing is 200ms.The 15min of each record circulation beginning is in the period, with the 0.05Hz electrical stimulation to guarantee the stable of fEPSP amplitude.Then, test compound is washed (wash in) with time of 30min, stimulate during this period with 0.05Hz and continue and the fEPSP recording occurring continuously.Wash back 30min, begin to induce LTP by the θ burst stimulation.Continue to write down 60min at least after LTP induces, LTP induces back 30min, and compound is washed out.All sections of writing down simultaneously all use identical time-program(me) to handle.Data according to record, (Synchroslice data acquisition and analysis (Synchroslice data acquisition and analysis) LRE) are calculated as with respect to the negative peak of the postsynaptic signal of baseline and by online mapping the amplitude of the fEPSP that brings out automatically by logging software.The signal of all records is digitized storage to carry out off-line analysis afterwards, calculates especially for the fEPSP negative slope.According to the single sweep (sweep) that stores, calculate the slope between maximum fEPSP amplitude 30% and 70%.For the data that can relatively obtain from the difference section, the fEPSP slope is pressed control value (100%) standardization.The effect that the material that uses causes is used Student ' s t check or Man-Huai Shi (Mann-Whitney) rank test, and if the detection statistics significance is p＜0.05 then be estimated as and have significance.Measurement under every kind of experiment condition repeats six times.Provide the result with mean value and standard deviation (SD) from n=5 section.
Use the organotypic slice culture thing of rat hippocampus and with three progressive concentrations (1 μ M, 10 μ M and 100 μ M; see Fig. 4 B-D) wash 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine; itself and false section (Fig. 4 A) of cultivating are compared, observe the blocking-up fully that LTP induces.On the contrary, in the contrast section that does not contain 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine, observe LTP and be induced to about 140% of pre-irritation level.The EPSP slope increases to some extent when this compound is removed, and the most obvious and very strong when 100 μ M concentration.
Embodiment 5: memory assessment in the body
Rat is one of standard testing system that is used for the old and feeble cognitive decline of being correlated with of clinical preceding assessment.Test compound has guaranteed stable plasma concentration by the lasting subcutaneous administration of infiltration micropump, therefore the most suitable prolonged application.In order to have the old and feeble relevant amnemonic example of research, can use the rat at 17 monthly ages.Perhaps can use transgenosis Model of Dementia animal (for example Alzheimer disease).Treatment situation according to animal is divided into many groups with them, only accepts medium (vehicle) in contrast for one group.The number of the group of the group scale-dependent research of 15 to 20 animals provides suitable statistics effect (statistical power).For two groups comparison, use t test statistics method, for the comparison that surpasses two groups, be used for the ANOVA of the correction of multiple testing.0.05 the P value to be considered to statistics significant.Experimentize in blind method mode, this comprises detection randomization and probe mark that calculator produces, and all experimenters do not understand up to the experiment end for the treatment identity, implements to separate with data analysis and experiment.Beginning to make animal adapt to for 1 week before the test.What pay special attention to is to make it fully obtain food and water at duration of test, and notes light-dark cycle.Before beginning to test one day will contain test compound or vectorial infiltration micropump is implanted.Can be by this test, the memory of body build-in test compound of the present invention strengthens ability.Below describe specially suitable in vivo studies in detail.
The spiral arm labyrinth: operation makes rat adapt to 4 days in the spiral arm labyrinth one day after.After laundering period animal was being tested 14 days in the spiral arm labyrinth, used four arm and four arms that are unkitted bait of adorning bait at random with little food ball.Run into the arm that is unkitted bait and made reference promnesia, enter identical arm once more and made work promnesia, with the arm of the dress bait that arrived before entering once more by note by note.When the arm of all dress baits was all entered or was arrived the time restriction of 480s, end of run.
The Sacktor disk: this test begins with adequacy test, in the adequacy test animal is not placed equipment 10min under the electric shock.Carry out continuous training test then, animal will be subjected to once shocking by electricity running into the electric shock zone at every turn therebetween.Training is made up of eight 10min training test, by 10min lounge in their tame cage (home cage) every separating.Then animal is tested in the single exploratory test.Exploratory test places this equipment by animal and time of initially entering between the electric shock district increases the conservation degree of measuring long time-histories storage area information.And the conservation degree of journey store information and long time-histories store information is all tested by the minimizing (this is performance fast after one period independent training time) that is used in the time in the electric shock zone in short-term.
Morris water maze (MWM): at first carried out the visualisation platforms test at first day.Clue outside the labyrinth stashed by curtain and platform and visual beacon are placed the first quartile of MWM.Animal is placed on relative quadrant place and allows its swimming find platform until it, maximum duration is 60s.If it arrives this platform, so it is taken out from water and allow it between each test in own cage rest 30s.Each that visualisation platforms is placed 4 quadrants is finished four tests.This provides the feature of zoologic sensorimotor and motivation, the latent period (latency) that arrives platform, the movement velocity that arrives platform and the parameter of distance.At second day animal training.Outside having visual labyrinth in the pond of clue, this animal is placed near one of original position of 4 random arrangements the wall.This animal should be swum to the platform in the submergence of fixed position.If it fails to find this platform in 60s, so it is placed 60s on platform.If it finds this platform in 60s, allow it on platform, stop 60s so.Change original position after each test.Find hiding platform with at least four test animal trainings every day.In 15s, arrive platform with enough fate animal trainings up to it.This provides the parameter about study and the ability of motor behavior, the latent period of runing away, swimming rate and swimming distance.Carry out exploratory test after training period.Remove platform, animal is placed the pond, in the relative quadrant of the quadrant of formal placement platform, and allow animal swimming 60s from the pond, shift out then.This provides about the percentage of time in the quadrant of MWM, the number of times that passes the assumed platform position, swimming time, swimming path length, the swimming that is parallel to wall, the number of times of contact wall and the parameter of swimming rate.
Claims (7)
1. the compound of a formula I:
Wherein
R
1For being selected from hydrogen, C
1-6The member of alkyl, hydroxyl and halogen;
R
2Be C
3-8Cycloalkyl,
R
3For being selected from hydrogen and C
1-6The member of alkyl;
And n is 0,1 or 2.
2. the compound of claim 1, described compound is 1-(1-chloro-8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine or 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.
3. one kind is improved the method that the subject remembers, and described method comprises the compound for the treatment of the claim 1 of effective dose to the patient that needs are arranged.
4. method for the treatment of illness relevant with the kinases that is selected from CSNK1E, CSNK1A1L, CSNK1D, MERTK, SLK, IRAK1, STK10, MAPK12, PHKG2, MAPK11, MET, AXL, STK32B, AURKC, CLK3, RPS6KA6, PDGFRB, KDR, CDK2 among the subject, described method comprises the compound for the treatment of the claim 1 of effective dose to the patient that needs are arranged.
5. the method for claim 4, wherein said illness is selected from anxiety, depression, bipolar disorder, unipolar disorders and posttraumatic stress disorder.
6. the method for claim 3, wherein said illness are selected from Alzheimer disease, schizophrenia and slight cognitive decline (MCI).
7. each method among the claim 3-6, wherein said compound is 1-(1-chloro-8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine or 1-(8-cyclohexyl-5 isoquinolin-sulfonyl) 2-methyl-piperazine.
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| CN105658653A (en) | 2013-08-23 | 2016-06-08 | 因赛特公司 | Furo- and thieno-pyridine carboxamide compounds useful as PIM kinase inhibitors |
| WO2015070170A1 (en) * | 2013-11-08 | 2015-05-14 | The Translational Genomics Research Institute | Compounds for cognitive enhancement and methods of use thereof |
| CN105085478B (en) * | 2014-04-28 | 2019-04-12 | 南京明德新药研发股份有限公司 | Isoquinolin sulphone amide derivative and its pharmaceutical composition and pharmaceutical applications |
| US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
| US9822124B2 (en) | 2014-07-14 | 2017-11-21 | Incyte Corporation | Bicyclic heteroaromatic carboxamide compounds useful as Pim kinase inhibitors |
| US9540347B2 (en) | 2015-05-29 | 2017-01-10 | Incyte Corporation | Pyridineamine compounds useful as Pim kinase inhibitors |
| AR105967A1 (en) | 2015-09-09 | 2017-11-29 | Incyte Corp | SALTS OF A PIM QUINASA INHIBITOR |
| WO2017059251A1 (en) | 2015-10-02 | 2017-04-06 | Incyte Corporation | Heterocyclic compounds useful as pim kinase inhibitors |
| MY196319A (en) | 2015-12-17 | 2023-03-24 | Merck Patent Gmbh | Polycyclic TLR7/8 Antagonists and use Thereof in the Treatment of Immune Disorders |
| WO2018031434A1 (en) * | 2016-08-08 | 2018-02-15 | Merck Patent Gmbh | Tlr7/8 antagonists and uses thereof |
| WO2019015608A1 (en) * | 2017-07-19 | 2019-01-24 | 南京明德新药研发股份有限公司 | Isoquinolinylsulfonyl derivative and use thereof |
| US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
| EP3868408A4 (en) * | 2018-10-15 | 2022-07-06 | National University Corporation Tokai National Higher Education and Research System | Antipsychotic and use thereof |
| CN115103672A (en) | 2020-01-09 | 2022-09-23 | 悟而喜制药公司 | Methods of treating wandering associated with cortical dementia |
| MX2022011519A (en) * | 2020-03-25 | 2022-10-07 | Woolsey Pharmaceuticals Inc | Methods of using rho kinase inhibitors to treat frontotemporal dementia. |
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| CA3180436A1 (en) * | 2020-06-25 | 2021-12-30 | Thomas Macallister | Methods of treating neurodevelopmental disorders |
| EP4181925A1 (en) * | 2020-07-14 | 2023-05-24 | Woolsey Pharmaceuticals, Inc. | Methods of treating proteinopathies |
| CA3193561A1 (en) * | 2020-10-22 | 2022-04-28 | Woolsey Pharmaceuticals, Inc. | Methods of treating 4-repeat tauopathies |
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| US20070179127A1 (en) * | 2005-08-30 | 2007-08-02 | Asahi Kasei Pharma Corporation | Sulfonamide compound |
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| WO2009151845A9 (en) | 2010-01-28 |
| US20110237600A1 (en) | 2011-09-29 |
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| US20100160297A1 (en) | 2010-06-24 |
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| CN102316737A (en) | 2012-01-11 |
| AU2009257926A1 (en) | 2009-12-17 |
| CA2723472A1 (en) | 2009-12-17 |
| EP2285217A1 (en) | 2011-02-23 |
| JP2011519973A (en) | 2011-07-14 |
| EP2285217A4 (en) | 2011-06-08 |
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